A visible-light activated secondary phosphine oxide ligand enabling Pd-catalyzed radical cross-couplings

Although transition metal-catalyzed reactions have evolved with ligand development, ligand design for palladium-catalyzed photoreactions remains less explored. Here, we report a secondary phosphine oxide ligand bearing a visible-light sensitization moiety and apply it to Pd-catalyzed radical cross-coupling reactions. The tautomeric phosphinous acid coordinates to palladium in situ, allowing for pseudo-intramolecular single-electron transfer between the ligand and palladium. Molecular design of the metal complexes aided by time-dependent density functional theory calculations enables the involvement of allyl radicals from π-allyl palladium(II) complexes, and alkyl and aryl radicals from the corresponding halides and palladium(0) complex. This complex enables radical cross-couplings by ligand-to-Pd(II) and Pd(0)-to-ligand single-electron transfer under visible-light irradiation.

P d-catalyzed cross-coupling is an important C-C bond formation methodology for the synthesis of pharmaceuticals, bioactive molecules, agrochemicals, and other functional molecules [1][2][3] . Transition metal catalysts have evolved along with ligand development. Ligand tuning expands the reactivity of transition metals, increases turnover number, and allows for reactions under mild conditions; therefore, the design and synthesis of electronically and sterically controlled ligands have created major breakthroughs in palladium chemistry 4 .
Owing to the development of LED light and visible-light photocatalysts, transition metal-catalyzed photoreactions have recently attracted the increased attention of many chemists. The Pd-catalyzed photoreactions can be classified into three modes (Fig. 1a), as follows: (1) those in which the external photocatalyst is the sole light-absorbing species to proceed along three pathways: oxidative single electron transfer (SET), reductive SET, and energy transfer 5-7 ; (2) those in which a Pd catalyst absorbs light [8][9][10] ; and (3) those in which the external photocatalyst and Pd catalyst absorb light and the energy transfers from the photocatalyst to the Pd-containing intermediate 11 (Fig. 1a). The generation of such a highly active palladium species enables versatile transformations. Moreover, although UV-light irradiation causes nonselective excitation of almost all materials, visiblelight irradiation can selectively excite photocatalysts or Pd complexes. Thus, reports of Pd-catalyzed photoreactions have increased in recent years. Although the reaction mechanisms of photoreactions are quite different from those of thermal reactions, phosphine ligands, which are well-studied and designed for thermal reactions, have been applied for photoreactions. The development of ligands that orient photoreactions is limited 12 . In addition, the absorption coefficient of the d → p transition 13,14 of the Pd(0) complex in the visible-light region is much smaller than that of other transition metals such as Ru and Ir photoredox catalysts (Fig. 1b). Hence, we expected that the development of ligands that absorb visible light will enhance the applications of transition metals.
To develop a ligand for photoreactions, we planned to synthesize a phosphine ligand with a photosensitive moiety. We first attempted to synthesize a tertiary phosphine bearing 9,10diphenylanthracene (DPA), but it was unstable and thus easily oxidized under air ( Supplementary Fig. 25). Therefore, we use a secondary phosphine oxide (DPAsphox (1)) as a pre-ligand (Fig. 1c), which acts as a ligand through the phosphorus atom after in situ tautomerization to phosphinous acids (DPAphos (1')) 15,16 . This ligand design enables the efficient absorption of visible light and pseudo-intramolecular electron or energy transfer to the metal center. Moreover, unlike photoredox catalysts, this metal complex enables a ligand-centered π → π* transition on DPAphos because the DPA moiety does not directly coordinate to palladium. Thus, we hypothesized that the excited DPAphos would generate Pd(I) by one-electron oxidation of Pd(0) via metal-to-ligand charge transfer (MLCT) or one-electron reduction of Pd(II) via ligand-to-metal charge transfer (LMCT) to promote further various radical reactions. The yielded DPA(•-) or (•+) exhibits opposite reactivities, indicating that different oxidation states of Pd(0 or II) can produce quite different reactivities.

Results
Computational studies of Pd complexes. We first calculated the absorption wavelength of the Pd(II)-DPAphos complex using time-dependent density functional theory (TD-DFT) calculations (Fig. 2a). The S 0 → S 1 absorption of Pd(II) complex (2) was calculated as the ligand-centered π → π* transition on DPA, and its wavelength expanded up to 500 nm, indicating that visiblelight irradiation enables selective excitation of the DPA moiety. We concluded that this excited DPA moiety in the Pd(II) complex enabled intramolecular one-electron reduction of Pd(II) to afford Pd(I) and DPA •+ via LMCT. Thus, we next individually compared the reduction potential of DPA and Pd(II). The reduction potential of DPA* (E 1/2 [DPA •+ /DPA*] = -1.68 V vs. SCE) (Supplementary Information, Section 1-7) was lower than that of allyl Pd(II) 17 and the one-electron reduction of 3 afforded 11.3 kcal/mol stable states (Fig. 2b), indicating that a rapid LMCT in the excited state of 2 would proceed to afford Pd(I) and DPA •+ (Fig. 2c).
We next calculated the absorption wavelength of Pd(0) complex (4); the ligand-centered π → π* transition on DPA was S 0 → S 2 at 383.7 nm, and the metal-centered d → p transition and d → π* MLCT were S 0 → S 1 at 395.6 nm (Fig. 2d). Although these metalcentered and MLCTs (S 0 → S 1 ) showed longer wavelengths than the ligand-centered transitions (S 0 → S 2 ), the oscillator strength of the S 0 → S 1 transition was 32 times smaller than that of the S 0 → S 2 transition, suggesting that the ligand-centered S 0 → S 2 transition favorably proceeds by irradiation under near 400 nm light. Furthermore, in the calculated S 1 state, the singlet biradicals were located on the singly occupied molecular orbital (SOMO) of the π* orbital of the DPA moiety and on the SOMO-1 of the d orbital of palladium (Fig. 2e), meaning that the radiationless transition from S 2 afforded the S 1 state via MLCT (Fig. 2f). This MLCT pathway is supported by the oxidation potential of DPA in the excited state (E 1/2 [DPA •-/DPA*] = +0.93 V vs. SCE) (Supplementary Information, Section 1-7), which is higher than that of Pd(PPh 3 ) 4 (E 1/2 [Pd(0)/Pd(I)] = -0.03 V vs. SCE) 18 . Therefore, the most favorable ligand-centered excitation (S 0 → S 2 ) facilitates the formation of 4(S 1 ) via MLCT (S 2 → S 1 ), and its high reduction potential (E calc [4 •+ /4(S 1 )] = -2.80 V vs. SCE) may cause a further radical reactions such as one-electron reduction of alkyl and aryl halides to generate the carbon-centered radicals.
Synthesis and experimental analysis of DPAsphox. DPAsphox 1 was synthesized, and the stability, spectroscopic and electrochemical properties, and coordination ability to palladium were evaluated. Pd-catalyzed C-P cross-coupling and esterification of 2-bromo-9,10-diphenylanthracene (5) with anilinium hypophosphite afforded ethyl phosphinate 6 in 79% yield 19 , and the subsequent nucleophilic substitution with phenyl magnesium bromide produced DPAsphox in 86% yield (Fig. 2g). The stability of DPAsphox was tested, and the purity was maintained for at least 1 week under refrigeration (Supplementary Table 7). Absorption and emission spectra of the synthesized DPAsphox revealed S 0 → S 1 absorption at 405 nm and S 1 → S 0 emission at 435 nm (2.85 eV) (Fig. 2h). In addition, cyclic voltammetry showed that the oxidation potential of DPAsphox was +1.33 V (vs. SCE) (Fig. 2i). Thus, the reduction potential of excited DPAsphox was estimated to be −1.52 V (vs. SCE) by Rehm-Weller formalism 20 . The coordination of DPAsphox to Pd(II) and Pd(0) complexes was next investigated by 31 P NMR (Fig. 2j). Stirring DPAsphox with [PdCl(allyl)] 2 and PPh 3 in DMF-d 7 for 1 hour led to the disappearance of the doublet peak at 18.5 ppm of DPAsphox, and the emergence of new peaks between 79.1 and 92.8 ppm, suggesting that DPAphos (1') derived from DPAsphox coordinates to palladium 15 . In addition, stirring with Pd(PPh 3 ) 4 also caused a peak shift between 79.1 and 79.8 ppm. Therefore, as we expected, DPAsphox can be a stable pre-ligand for DPAphos to become a Pd-DPAphos complex.
Radical cross-couplings using a Pd(II) complex. We performed Pd-catalyzed radical cross-coupling reactions under visible-light irradiation to demonstrate the utility of DPAsphox. We first verified the reactivity of the allyl-Pd(II)-DPAphos complex ( Table 1 and Fig. 3). Using N-phenyl-1,2,3,4-tetrahydroisoquinoline (7a) and allyl methyl carbonate (8a), C-allylated product 9a was obtained in 75% yield under purple-light irradiation (400 nm) ( Table 1, entry 1) 21 . Irradiation with blue LED light (450 nm) showed the similar performance to give the product (9a) in 76 % yield (entry 2). Control experiments in entries 3 and 4 indicated that Pd catalyst and visible-light irradiation are essential for the allylation reaction. When using ligands such as PPh 3 , DPEphos, and Xantphos, which cannot absorb visible light by themselves, no allylated compound (9a) was obtained (entries 5 and 6). The reaction with DPA instead of DPAsphox also afforded 9a in 25% yield (entry 7), suggesting that the pseudo-intramolecular electron transfer of DPAphos improved the yield in comparison with intermolecular SET with DPA.
Thus, we next carried out a fluorescence quenching study of DPAphos and DPA to investigate the efficiency of the SET from DPAphos to Pd(II) (Fig. 3a, b). The absorption spectrum of the mixture of DPAsphox, [PdCl(allyl)] 2 , and PPh 3 (solid red line) showed the same intensity as DPAsphox (dotted red line) at around 400 nm, meaning that the DPA moiety of the DPAphos absorbs the light (Fig. 3a). In contrast, the emission intensity was strongly suppressed by the coordination of DPAphos to palladium, clearly suggesting that quenching proceeded via LMCT from excited DPAphos to Pd(II). On the other hand, no quenching was observed when we performed the same spectroscopic study using DPA instead of DPAsphox (Fig. 3b). The results of these quenching studies suggest that coordination of DPAphos to Pd(II) enables highly efficient LMCT by pseudointramolecular electron transfer.
Radical cross-couplings using a Pd(0) complex. The reactivity and spectroscopic properties of the Pd(0) complex were next evaluated under blue-light irradiation ( Table 2 and Fig. 4). Control experiments of the Heck reaction were performed with styrene (10a) and unactivated tertiary alkyl bromide (11a) ( Table 2) [23][24][25][26] . The addition of 5 mol % of Pd(PPh 3 ) 4 and DPAsphox provided βalkylated styrene (12a) in 79% yield under 5 W blue LED lights (entry 1). In situ generation of Pd(0) complex from 5 mol % of Pd(PPh 3 ) 2 Cl 2 , PPh 3 , and DPAsphox improved the yield of 12a in 93% (entry 2). Under conditions without DPAsphox (entry 3) and with DPA instead of DPAsphox (entry 4), 12a was produced in low yield, indicating that DPAsphox plays an important role as a visiblelight-activated ligand. Shang and Fu reported this kind of photoinduced Heck reaction, in which they achieved a high yield and broad substrate generality using Xantphos; 25 the reaction required intense light, however, such as a 36 W blue LED light, because Xantphos does not absorb visible light. Thus, under our 5 W blue LED condition, the photoreaction with Xantphos gave the product in 57% yield (entry 5).
Thus, we next carried out a UV-Vis spectroscopic and fluorescence quenching study using Pd(0) and DPAsphox to clarify the interaction between them (Fig. 4a). The absorption intensity of the mixture of Pd(PPh 3 ) 4 and DPAsphox was stronger (solid red line) than that of Pd(PPh 3 ) 4 alone (blue line) because of the π → π* transition of DPAphos (dotted red line). The emission of DPAphos (dotted red line) was clearly suppressed in the presence of Pd(PPh 3 ) 4 (solid red line), indicating that pseudo-intramolecular quenching occurred in the Pd(0)-DPAphos complex. Additionally, tert-BuBr (11a) did not affect the absorption and emission spectra ( Supplementary  Figs. 37, 38), suggesting that no EDA complex formed between Pd(0) and 11a. Furthermore, the mixture of Pd(PPh 3 ) 4 and DPA (solid black line) showed almost no change in the absorption and emission spectra compared with DPA alone (dotted black line) (Fig. 4b) similar to the Pd(II) complex. Together, these results support the high efficiency of our visible-light-activated ligand.
Dehalogenative hydrogenations of aryl chloride and bromide were demonstrated (Fig. 5b). The hydrogenation of 2-chlorobenzonitrile proceeded in 87% yield using N-methylpyrrolidone (NMP) as a solvent and a hydrogen donor (17a) 28 . 9-Bromophenanthrene and methyl 2-bromobenzoate yielded the corresponding arenes in 93% and 89% yields (17b, c). In addition, our reaction system selectively hydrogenated halide on arenes in the presence of terminal olefin and benzyl ether in the substrates (17d, e).
Reaction mechanisms of Pd-catalyzed radical cross-couplings. Finally, the reaction mechanisms of α-allylation of amines with Pd(II) (Fig. 3) and a photo-Heck reaction with Pd(0) (Fig. 4) are considered and compared in Fig. 6. The process involving light is the ligand-centered excitation for both reactions, namely the π → π* transition of the DPA moiety, but the subsequent quenching path differs between them: a one-electron reduction of Pd(II) (LMCT) and a one-electron oxidation of Pd(0) (MLCT).
In the allylation reaction, oxidative addition of allyl methyl carbonate 8 to Pd(0) complex A forms redox-active π-allyl Pd(II) complex B at room temperature 29 . Although the direct reduction pathway of 8 by excited Pd(0) complex A cannot be excluded, the formation of π-allyl Pd(II) complex B is plausible because no ligands other than DPAsphox functioned (Table 1) and allyl alcohol was also applicable for this allylation reaction (Fig. 3c) 30 .
The eliminated methyl carbonate generates methoxide anions through decarboxylation and acts as a base. The highly efficient pseudo-intramolecular one-electron reduction (LMCT) from the S 1 state (C) generated the biradical state D; fluorescence quenching supported this process (Fig. 3b). The following oneelectron oxidation of amine (7) by DPA •+ afforded the corresponding 7 •+ . Then, the free radical [7 − H] • generated from 7 •+ by deprotonation reacted with the allyl-Pd(I) complex (E) (path A) or free allyl radical (path B) to give the product 9 and complex A 21 .
On the other hand, in the reaction mechanisms of the Pdcatalyzed photo-Heck reaction, Pd(I) cation species (H) would be    (Fig. 2d), indicating that the S 0 → S 2 → S 1 transition would be the primary excitation mechanism of this complex. Because the DPA • − moiety of H has a high reduction potential, alkyl bromide 11 31 is readily reduced to give alkyl radical and Pd(I) complex I. After the addition of alkyl radical to styrene 10 (I → J) and the following bromo atom transfer from Pd(I) to the benzyl radical (J → K), Pd(0) complex F is regenerated, and β-alkylated styrene 12 is provided by elimination of HBr, which is supported by the KIE experiment ( Supplementary Information, Section 1-15) 25,26 .

Discussion
A visible-light-activated secondary phosphine oxide ligand was developed for Pd-catalyzed radical cross-couplings. The ligandcentered π → π* transition of DPAphos promoted allyl radicalmediated cross-coupling via LMCT in the allyl Pd(II) complex, and alkyl and aryl radical-mediated cross-couplings via MLCT in the Pd(0) complex. The efficient SET was observed by spectroscopic studies as a strong quenching of the fluorescence emission of DPAphos. This was achieved by the visible-light-sensitizing moiety (DPA) in the secondary phosphine oxide ligand. Our strategy for designing a visible-light-activated ligand and metal complexes showed potential for tuning the electronic state of transition metals under visible-light irradiation. Further development of ligands to orient transition-metal-catalyzed photoreactions is expected.

Methods
General information. NMR spectra were recorded on JEOL-JMN-ECS 400 or ECZ 400 spectrometers. Data for NMR are reported as follows: chemical shift (δ ppm), multiplicity (s singlet, br-s broad singlet, d doublet, t triplet, q quartet, and m multiplet), coupling constants (Hz), and integration. Chemical shifts are reported in the scale relative to TMS (0.0 ppm) for 1 H NMR and the solvent signal (CHCl 3 (77.0 ppm)) for 13 C NMR. 19 F and 31 P NMR spectra are referenced to external hexafluorobenzene and 85% phosphoric acid. Infrared (IR) spectra were recorded on a Fourier transform infrared spectrophotometer equipped with ATR. Highresolution mass spectra were measured on a JEOL AccuTOF LC-plus JMS-T100LP instrument (ionization method: ESI  were measured by a JASCO V-730 spectrophotometer and FP-8500 spectrofluorometer. Column chromatographic purification was performed with silica gel 60 N (spherical, neutral 40-50 μm), and preparative TLC purification was performed with TLC silica gel 60 F 254 . The Pd-catalyzed reactions were carried out with standard Schlenk techniques under Ar atmosphere. Unless otherwise noted, photochemical reactions were performed with degassed solvents by freeze-pumpthaw cycles three times.
Computational methods. All calculations were performed with the Gaussian 16 program 32 . Structure optimizations were carried out at 298.15 K, using the MN15 33 functional with an ultrafine grid and the SDD 34 (for Pd) and 6-31 G(d) (for the other atoms) basis sets. DMF (for Pd(II) complex) and N,N-dimethylacetamide (DMA) (for Pd(0) complex) were used as implicit solvents using PCM 35 as a solvation model. Harmonic vibrational frequencies were computed at the same level of theory to confirm that no imaginary vibration was observed for the optimized structure. Single-point energy calculations were performed for all geometries at 298.15 K, using the ωB97X-D 36 functional with an ultrafine grid and the SDD (for Pd) and 6-311 + G(d,p) (for the other atoms) basis sets with the same solvation model. The Gibbs free energy was calculated by the sum of total electronic energy in the single-point energy calculation and the thermal correction energy in the frequency calculation. All molecular orbitals were computed at an isovalue of 0.02.